Plasma Clusterin as a Potential Link between Diabetes and Alzheimer Disease

Objective: Plasma clusterin, a promising biomarker of Alzheimer disease (AD), has been associated with diabetes mellitus (DM). However, clusterin has not been investigated considering a relationship with both DM and AD. In this study, we aimed to investigate the individual and interactive relationships of plasma clusterin levels with both diseases. Design: Cross-sectional observation study. Methods: We classified participants by the severity of cognitive (normal cognition, mild cognitive impairment [MCI], and AD) and metabolic (healthy control, prediabetes, and DM) impairments. We evaluated the cognitive and metabolic functions of the participants with neuropsychological assessments, brain magnetic resonance imaging, and various blood tests, to explore potential relationships with clusterin. Results: Plasma clusterin levels were higher in participants with AD and metabolic impairment (prediabetes and DM). A two-way ANCOVA revealed no synergistic, but an additive effect of AD and DM on clusterin. Clusterin was negatively correlated with cognitive scores. It was also associated with metabolic status indicated by glycated hemoglobin A1c (HbA1c), the Homeostatic Model Assessment for Insulin Resistance index, and fasting C-peptide. It showed correlations between medial temporal atrophy and periventricular white matter lesions, indicating neurodegeneration and microvascular insufficiency, respectively. Further mediation analysis to understand the triadic relationship between clusterin, AD, and DM revealed that the association between DM and AD was significant when clusterin is considered as a mediator of their relationship. Conclusions: Clusterin is a promising biomarker of DM as well as of AD. Additionally, our data suggest that clusterin may have a role in linking DM with AD as a potential mediator.